ABSTRACT Asthma is a highly prevalent airway disease that is a major public health problem for which available treatment options are inadequate. Endogenous nitrated fatty acids (NFAs), thought to be produced from NO, have recently been identified as important bioactive compounds present in human plasma. Although investigation of their biological activities is at an early stage, evidence is accumulating that they are potent anti-inflammatory molecules. Our preliminary data show that administration of exogenous NFAs can significantly attenuate pathophysiologic manifestations in a murine model of allergic airway disease, whereas inhibiting endogenous NFA synthesis exacerbates allergic responses. NFAs activate the nuclear transcription factor peroxisome proliferator-activated receptor- (PPAR-) in some cell types, and we have found that allergic responses are exacerbated when PPAR- is genetically eliminated but are attenuated by overexpression of PPAR- in airway epithelial cells in vivo. Accordingly, we propose to test the hypothesis that activation of airway epithelial cell PPAR- by nitrated fatty acids significantly suppresses the effects of allergic airway disease, including inflammation and mucus production. Our Specific Aims are: 1) to determine the extent to which NFAs modulate PPAR- activity in the lung and the severity of murine allergic airway disease, for which we will use mice constitutively lacking all three isoforms of nitric oxide synthase (triple NOS knockout) and therefore expected to lack NFAs; 2) to determine whether PPAR- activation in airway epithelial cells mediates NFAs' ability to inhibit effects of allergen challenge in murine allergic airway disease, for which we will utilize mice with PPAR- either knocked out or overexpressed selectively in airway epithelial cells; and 3) to determine whether NFAs inhibit chemokine and mucus production in cultured human airway epithelial cells and the extent to which these effects are mediated through PPAR--dependent and/or PPAR--independent mechanisms, for which we will use gene silencing and chemical inhibition to suppress PPAR- while testing for activation of other signaling pathways. For Aims 1 and 2 we will utilize an established murine model of allergic airway disease induced by cockroach allergen, while Aim 3 will be carried out in vitro using well differentiated primary human bronchial epithelial cells grown at an air-liquid interface. Validation of our hypothesis will identify and elucidate the mechanisms through which a novel endogenous substance modulates the severity of allergic airway disease and may lead to new therapeutic avenues and treatments for asthma.